Cututtukan da sauro ke yadawa na ci gaba da zama babbar matsala a fannin lafiyar jama'a a duniyaƘara juriyar ƙwayoyin cuta, kamar Culex pipiens pallens, ga magungunan kwari na gargajiya ya ƙara ta'azzara wannan matsalar. A cikin wannan binciken, an tsara jerin sabbin ƙwayoyin thiophene-isoquinolinone hybrids, an haɗa su, an kimanta su a matsayin ƙwayoyin cuta masu yuwuwar kamuwa da su. Daga cikin mahaɗan da aka haɗa, abubuwan da aka samo asali daga 5f, 6, da 7 sun nuna babban aikin kashe ƙwari akan tsutsar Culex pipiens pallens tare da ƙimar LC₅₀ na 0.3, 0.1, da 1.85 μg/mL, bi da bi. Abin lura, duk abubuwan da aka samo asali daga thiophene-isoquinolinone goma sha biyu sun nuna guba mafi girma fiye da magungunan kashe ƙwari na organophosphate chlorpyrifos (LC₅₀ = 293.8 μg/mL), wanda ya tabbatar da mafi girman gubar waɗannan mahaɗan. Abin sha'awa, matsakaiciyar 1a ta roba (mai matsakaicin thiophene semiester) ta nuna mafi girman ƙarfin aiki (LC₅₀ = 0.004 μg/mL), kuma kodayake ba a inganta shi sosai ba tukuna, ƙarfinsa har yanzu ya wuce na duk abubuwan da aka samo asali na ƙarshe. Nazarin ilimin halittu na injiniya ya nuna alamun gubar jijiyoyi masu ƙarfi, yana nuna rashin aikin cholinergic. Kwaikwayon ƙwayoyin halitta da kwaikwayon yanayin ƙwayoyin halitta sun tabbatar da wannan lura, suna bayyana hulɗa mai ƙarfi tare da acetylcholinesterase (AChE) da mai karɓar nicotinic acetylcholine (nAChR), yana nuna yiwuwar hanyar aiki biyu. Lissafin ka'idar aiki mai yawa (DFT) ya ƙara tabbatar da kyawawan halaye na lantarki da amsawar mahaɗan aiki. Bambancin tsarin da kuma yawan ƙarfin wannan jerin mahaɗan na iya rage haɗarin juriyar giciye da sauƙaƙe dabarun sarrafa juriya ta hanyar juyawa ko haɗuwa. Gabaɗaya, waɗannan sakamakon sun nuna cewa hybrids na thiophene-isoquinolinone zaɓi ne mai ban sha'awa don haɓaka larvicides na gaba waɗanda ke niyya ga hanyoyin neurophysiological na ƙwayoyin kwari.
Sauro suna daga cikin mafi ingancin masu yada cututtuka masu yaduwa, suna yada nau'ikan cututtuka masu haɗari da kuma barazana ga lafiyar jama'a ta duniya. Nau'o'in kamar Culex pipiens, Aedes aegypti, da Anopheles gambiae an san su musamman wajen yada ƙwayoyin cuta, ƙwayoyin cuta, da ƙwayoyin cuta, suna haifar da miliyoyin cututtuka da mace-mace da yawa a kowace shekara. Misali, Culex pipiens babban mai yada arboviruses ne kamar kwayar cutar West Nile da kwayar cutar St. Louis encephalitis, da kuma cututtukan parasitic kamar zazzabin cizon sauro. Binciken da aka yi kwanan nan ya kuma nuna cewa Culex pipiens yana taka muhimmiyar rawa a cikin vector da watsa ƙwayoyin cuta masu cutarwa kamar Bacillus cereus da Staphylococcus warwickii, waɗanda ke gurɓata abinci da kuma ƙara ta'azzara matsalolin lafiyar jama'a. Sauro mai yawa yana iya daidaitawa, rayuwa, da kuma juriyar hanyoyin sarrafa su yana sa su wahala a sarrafa su kuma yana haifar da barazana mai ɗorewa.
Magungunan kashe kwari masu sinadarai muhimmin kayan aiki ne wajen shawo kan sauro, musamman a lokacin barkewar cututtukan da sauro ke haifarwa. Ana amfani da nau'ikan magungunan kashe kwari iri-iri, ciki har da pyrethroids, organophosphates, da carbamates, don rage yawan sauro da kuma yaɗuwar cututtuka. Duk da haka, yawan amfani da waɗannan sinadarai na tsawon lokaci ya haifar da matsalolin muhalli da lafiyar jama'a, ciki har da katsewar yanayin halittu, illa ga nau'ikan da ba a kai hari ba, da kuma saurin ci gaban juriyar kwari ga sauro.11, 12, 13, 14Wannan juriyar ta rage tasirin magungunan kwari na gargajiya sosai, yana nuna buƙatar gaggawa ta samar da ingantattun hanyoyin magance waɗannan barazanar da ke tasowa.11, 12, 13, 14Domin magance waɗannan ƙalubale masu tsanani, masu bincike suna juyawa zuwa wasu dabarun kamar sarrafa kwayoyin halitta, injiniyan kwayoyin halitta, da kuma kula da ƙwayoyin cuta masu haɗaka (IVM). Waɗannan hanyoyin suna nuna alƙawarin dorewar sarrafa sauro na dogon lokaci. Duk da haka, a lokacin annoba da gaggawa, hanyoyin sinadarai suna da mahimmanci don hanzarta amsawa.
Isoquinoline alkaloids suna da muhimman sinadarai masu ɗauke da nitrogen waɗanda aka rarraba a cikin ƙasar shuka, waɗanda suka haɗa da iyalai kamar Amaryllidaceae, Rubiaceae, Magnoliaceae, Papaveraceae, Berberidaceae, da Menispermaceae.30 Nazarin da aka yi a baya sun tabbatar da cewa isoquinoline alkaloids suna da ayyuka daban-daban na halitta da fasaloli na tsari, waɗanda suka haɗa da maganin kwari, maganin ciwon suga, maganin ƙari, maganin fungal, maganin kumburi, maganin kashe ƙwayoyin cuta, maganin kashe ƙwayoyin cuta, maganin kashe ƙwayoyin cuta, maganin kashe ƙwayoyin cuta, maganin kashe ƙwayoyin cuta, maganin kashe ƙwayoyin cuta, maganin kashe ƙwayoyin cuta, da kuma tasirin kariya daga jijiyoyi.
A cikin wannan binciken, ƙimar χ² ga dukkan mahaɗan sun kasance ƙasa da ma'aunin mahimmanci, kuma ƙimar p sun kasance sama da 0.05. Waɗannan sakamakon sun tabbatar da amincin kimantawar LC₅₀ kuma suna nuna cewa koma-baya na yuwuwar zai iya bayyana dangantakar da aka lura da martanin kashi-kashi yadda ya kamata. Saboda haka, ƙimar LC₅₀ da fihirisar guba (TIs) da aka ƙididdige bisa ga mahaɗan da suka fi aiki (1a) suna da matuƙar aminci kuma sun dace da kwatanta tasirin guba.
Domin kimanta hulɗar da aka yi tsakanin sabbin abubuwan da aka haɗa na thiophene-isoquinolinone guda 12 da kuma wanda ya riga su 1a tare da manyan abubuwan da ake nufi da neuronal sauro guda biyu—acetylcholinesterase (AChE) da kuma nicotinic acetylcholine receptor (nAChR)—mun gudanar da tsarin docking na kwayoyin halitta. An zaɓi waɗannan abubuwan ne bisa ga alamun cutar neurotoxic da aka lura a cikin gwaje-gwajen mutuwar tsutsa, wanda ke nuna rashin kyawun siginar jijiyoyi. Bugu da ƙari, kamanceceniya tsakanin waɗannan abubuwan da aka haɗa da organophosphates da neonicotinoids yana ƙara tallafawa zaɓin da aka fi so na waɗannan abubuwan da aka haɗa, yayin da organophosphates da neonicotinoids ke haifar da tasirinsu mai guba ta hanyar hana AChE da kunna nAChR, bi da bi.
Bugu da ƙari, wasu mahaɗan (ciki har da 1a, 2, 5a, 5b, 5e, 5f, da 7) suna hulɗa da SER280. Rassan SER280 suna da hannu wajen tsara yanayin tsarin lu'ulu'u kuma ana kiyaye su a cikin sake fasalin BT7. Wannan bambancin yanayin hulɗa yana nuna sauƙin daidaitawar waɗannan mahaɗan a cikin wurin aiki, tare da SER280 da GLU359 mai yiwuwa suna aiki a matsayin wuraren haɗin gwiwa masu daidaitawa a ƙarƙashin yanayin docking. Hulɗar da aka saba gani tsakanin abubuwan da aka samo asali da maɓallan ragowar kamar GLU359 da SER280, waɗanda sune sassan triad na SER-HIS-GLU catalytic triad a cikin acetylcholinesterase na ɗan adam (AChE), yana ƙara tallafawa hasashen cewa waɗannan mahaɗan na iya yin tasirin hanawa mai ƙarfi akan AChE ta hanyar ɗaure su zuwa wurare masu mahimmanci na catalytic.29,61,64
Abin lura shi ne, mahaɗin 6 da abin da ya riga shi 1a sun nuna mafi ƙarfin aiki akan tsutsotsi a cikin bioassay, suna nuna mafi ƙarancin ƙimar LC₅₀ tsakanin mahaɗan da ke cikin jerin. A matakin kwayoyin halitta, mahaɗin 6 yana nuna muhimmiyar hulɗa da chlorpyrifos a wurin GLU359, yayin da mahaɗin 1a ya haɗu da BT7 da aka sake shan ta ta hanyar haɗin hydrogen zuwa SER280. Dukansu GLU359 da SER280 suna nan a cikin asalin tsarin ɗaure kristal na BT7 kuma sune sassan triplet na catalytic na acetylcholinesterase (SER-HIS-GLU), yana nuna mahimmancin aikin waɗannan hulɗar wajen kiyaye aikin hana mahaɗan (Hoto na 10).
Kamanceceniya da aka lura a wuraren da ke ɗaurewa tsakanin abubuwan da aka samo daga BT7 (gami da BT7 na asali da waɗanda aka sake haɗa su) da chlorpyrifos, musamman a wuraren da ke da mahimmanci ga ayyukan catalytic, yana nuna cewa akwai wata hanyar da aka saba amfani da ita wajen hana waɗannan mahaɗan. Gabaɗaya, waɗannan sakamakon sun tabbatar da mahimmancin yuwuwar abubuwan da aka samo daga thiophene-isoquinolinone a matsayin masu hana acetylcholinesterase masu ƙarfi saboda hulɗarsu da aka adana da kuma waɗanda suka dace da yanayin halitta.
Ƙarfin alaƙa tsakanin sakamakon docking na ƙwayoyin halitta da sakamakon bioassay na tsutsa ya ƙara tabbatar da cewa acetylcholinesterase (AChE) da nicotinic acetylcholine receptor (nAChR) su ne manyan abubuwan da ke haifar da guba ga ƙwayoyin cuta na abubuwan da aka haɗa na thiophene-isoquinolinone. Duk da cewa sakamakon docking yana ba da mahimman bayanai game da kusancin receptor-ligand, ya kamata a gane cewa kuzarin ɗaurewa kaɗai bai isa ya bayyana cikakken tasirin kashe kwari a cikin jiki ba. Bambance-bambance a cikin ƙimar LC₅₀ tsakanin mahaɗan da ke da halaye iri ɗaya na docking na iya zama saboda dalilai kamar kwanciyar hankali na rayuwa, sha, samuwar halittu, da rarrabawa a cikin kwari.⁶⁰,⁶⁴Duk da haka, ƙirar tsarin tunani, ƙarfin haɗin masu karɓa da aka kwaikwayi ta hanyar kwaikwayon kwamfuta, da kuma ƙarfin ayyukan halittu suna goyon bayan ra'ayin cewa AChE da nAChRs sune manyan masu shiga tsakani na gubar da aka lura a cikin jijiyoyi.
A ƙarshe, ƙwayoyin thiophene-isoquinolinone da aka haɗa suna da muhimman abubuwan gina jiki da aiki waɗanda suka dace da sanannun magungunan kashe kwari masu aiki. Ikonsu na ɗaurewa da acetylcholinesterase (AChE) da masu karɓar acetylcholine na nicotinic (nAChRs) yadda ya kamata ta hanyar hanyoyin hulɗa masu dacewa yana nuna yuwuwarsu a matsayin magungunan kashe kwari masu manufa biyu. Wannan tsarin biyu ba wai kawai yana haɓaka ingancin maganin kwari ba ne, har ma yana ba da dabarar da za ta shawo kan hanyoyin juriya da ake da su, wanda hakan ya sa waɗannan mahaɗan su zama masu alƙawarin haɓaka magungunan hana sauro na gaba.
Ana amfani da kwaikwayon ƙwayoyin halitta (MD) don tabbatarwa da faɗaɗa sakamakon toshewar ƙwayoyin halitta, yana samar da kimantawa mai ma'ana da dogaro da lokaci na hulɗar ligand-manufa a ƙarƙashin yanayin zahiri na ilimin halittar jiki. Kodayake toshewar ƙwayoyin halitta na iya samar da bayanai masu mahimmanci na farko kan matsayi da alaƙar da za a iya ɗauka, samfurin tsayayye ne kuma ba zai iya la'akari da sassaucin mai karɓa ba, ƙarfin narkewa, ko canjin lokaci a cikin hulɗar ƙwayoyin halitta. Saboda haka, kwaikwayon MD muhimmin hanya ce ta dacewa don tantance kwanciyar hankali mai rikitarwa, ƙarfin hulɗa, da canje-canje na tsari a cikin ligands da sunadarai akan lokaci.60,62,71
Dangane da mafi kyawun halayen ɗaure su ga acetylcholinesterase (AChE) idan aka kwatanta da nicotinic acetylcholine receptor (nAChR), mun zaɓi ƙwayar iyaye 1a (tare da mafi ƙarancin ƙimar LC₅₀) da kuma mafi yawan sinadarin thiophene-isoquinoline 6 don kwaikwayon ƙwayoyin halitta (MD). Manufar ita ce a tantance ko yanayin ɗaure su a wurin aiki na AChE ya kasance mai karko sama da ns 100 na kwaikwayo da kuma kwatanta halayen ɗaure su da na chlorpyrifos da kuma mai hana AChE BT7 mai dawowa.
Kwaikwayon yanayin ƙwayoyin halitta sun haɗa da karkacewar tushen matsakaicin murabba'i (RMSD) don tantance daidaiton hadaddun abubuwa; karkacewar tushen matsakaicin murabba'i na canzawa (RMSF) don nazarin sassaucin ragowar abubuwa; da kuma nazarin hulɗar ligand-acceptor don tantance daidaiton haɗin hydrogen, hulɗar hydrophobic, da hulɗar ionic (Bayanan Ƙarin Bayani). Kodayake ƙimar RMSD da RMSF ga duk ligands sun kasance a cikin kewayon da ke da kwanciyar hankali, wanda ke nuna babu wani canji mai mahimmanci a cikin hadaddun AChE-ligand (Hoto na 12), waɗannan sigogi kaɗai ba su isa su bayyana cikakken bambance-bambancen da ke cikin nauyin ɗaurewa tsakanin mahaɗan ba.
Lokacin Saƙo: Disamba-15-2025